Heparin is a highly sulfated, polydisperse, .alpha.-(1.fwdarw.4)-linked copolymer of uronic acid and glucosamine. Jacques, Science 206: 528-33, 1979. Heparin is synthesized as a proteoglycan of approximately one million daltons molecular weight. Heparin is attached to a protein core. The protein core is removed in commercial processing, to obtain glucosaminoglycan heparin (average molecular weight 10,000 to 14,000 daltons).
Heparin's major application is as an anticoagulant. However, heparin has a multiplicity of other biological activities, including: (1) the ability to regulate angiogenesis (Folkman et al., Science, 221: 719-25, 1983); (2) the ability to regulate other cell growth and proliferation processes; (3) the ability to activate and release plasma lipoprotein lipase (Merchant et al., Atherosclerosis, 62: 151-58, 1986); and (4) the ability to inhibit complement cascade.
In 1929, Ecker and Gross first demonstrated the capacity of heparin to regulate complement activation. Subsequently, other investigators demonstrated multiple sites in the classical as well as the alternative-amplification pathways of complement at which heparin may act. Heparin's anticoagulant activity is mediated through a specific oligosaccharide sequence on the heparin polymer capable of binding antithrobin III. Heparin's structure activity relationship on the complement cascade system, however, is still poorly understood.
Heparin's complement cascade inhibiting activity can be used for a variety of functions to reduce the host's immune response. Organ transplant rejection is an example of an appropriate immune response which is detrimental to the individual host (i.e., mammals). Similarly, there are a variety of autoimmune diseases which result from the immune response attacking the individual's own cells. These immune and autoimmune diseases represent a class of diseases which are often difficult to treat effectively. Although there are a number of drugs which can be immune suppressant, none of the currently available therapeutic agents are adequate to control or specifically inhibit complement cascade activation. The inhibition of complement may be an important aspect in a variety of immune disorders. The diseases in which a substance that inhibits the complement cascade system may be therapeutically useful include paroxysmal nocturnal hemoglobulimurea, rheumatoid arthritis (in which the substance might be administered directly into a joint capsule to prevent complement activation), and hereditary angioedema (in which a deficiency in complement control protein leads to an active complement consumption). Other diseases include septic shock, rheumatoid arthritis and systemic lupus erythematous.
Heparin's anticoagulant activity has been demonstrated to be associated with the presence in its structure of a specific oligosaccharide sequence for the binding of antithrombin III. Once bound to heparin, antithrombin III can then inhibit a number of blood coagulation factors, and thus prevent the coagulation of blood.
Heparin's anticomplement activity is mediated by binding to a variety of complement cascade proteins and thereby regulates both the classical and alternate cascade pathways. Heparin and heparin oligosaccharides inhibit a portion of the complement cascade by inhibiting the generation of cell-bound amplification pathway C3 convertases, C3b,Bb, C3b,Bb,P and C3b,Bb,Nef. Heparin's anticomplement activity interferes with the binding site on the C3b. Furthermore, heparin prevents the fluid phase consumption of B by D in the presence of C3b, again indicating a direct action on C3b.
Accordingly, there is a need in the art for therapeutic agents with heparin-like anticomplement activity and greatly reduced (e.g., 10% or less) of heparin's anticoagulant activity on a weight basis. This invention fulfills the need.